Mutations in Presenilin-1 (PS1) are linked to early onset of familial Alzheimer's disease (FAD) and lead to increased production of Abeta42, a peptide that is accumulated during aging and plays a critical role in AD pathogenesis. PS1 is a multi- pass transmembrane protein that is essential for mouse embryonic development and is required for Abeta peptide generation. PS1 also interacts with beta-catenin and has been implicated in regulating beta-catenin stability in vitro. The in vivo function of PS1 in the adult central nervous system and other tissues is poorly understood, due to the early lethal phenotype of the PS1 null mouse. We have reported that transgenic mouse lines expressing either the wild-type human PS1 protein or PS1 containing the A246E FAD mutation, under the neuronal-specific human Thy-1 promoter, can protect the PS1 null mouse against embryonic lethality and simultaneously restore Abeta expression. This "rescue" system allows us to further define PS1 in vivo activities by introducing specific modifications, such as PS1 mutations affecting Abeta synthesis or beta-catenin interaction respectively. It also offers us a unique opportunity to study the effect of PS1 loss-of-function in adult peripheral tissues of existing mice as they are rescued by a neuronal specific expression of the PS1 transgene. Our preliminary data indicate that lack of PS1 expression in the skin of these mice leads to epidermal hyperplasia and neoplasm, suggesting that PS1 may play an important role in skin tissue, possibly through beta-catenin signaling pathway. Our long-term objective is to use our established rescue system to dissect multiple pathways which PS1 seems to participate in vivo. The specific aims of the proposal are: 1] To explore the molecular mechanism of PS1 activity in adult epidermis; 2] To identify the in vivo significance of PS1- beta-catenin interaction; 3] To determine whether the developmental activity and Abeta generating property of PS1 can be differentiated. We believe that these studies will advance our understanding of the physiological function of PS1 and the pathogenic mechanism of Alzheimer's disease.